Studies from this laboratory have led to a unifying hypothesis of body fluid volume regulation. This hypothesis emphasizes the importance of the integrity of the arterial circulation as the primary determinant of renal sodium and water excretion and thus body fluid volume regulation. An impairment in arterial circulatory integrity, so-called arterial underfilling, can be mediated by either a decrease in cardiac output or peripheral arterial vasodilation. We have proposed that two important clinical states, namely pregnancy and cirrhosis, are associated with arterial underfilling resulting from primary peripheral arterial vasodilation. In support of this hypothesis are associated hemodynamic, hormonal and renal excretory characteristics of pregnancy and cirrhosis which can be mimicked by arterial vasodilation. These include increased cardiac output secondary to afterload reduction; decreased mean arterial pressure secondary to primary arterial vasodilation; stimulation of the neurohumoral response to arterial underfilling including activation of the renin-angiotensin-aldosterone axis, the sympathetic nervous system and the non-osmotic release of vasopressin; and renal sodium and water retention. Pivotal to this arterial vasodilation hypothesis is the identification of the specific vasodilator(s) that may occur in pregnancy and cirrhosis. The quantification of the role of any vasodilator must them be assessed by examining the hemodynamic, humoral and renal alterations which occur in association with blockade of the specific vasodilator. In the present study research protocols have been designed to evaluate the role of nitric oxide in the peripheral arterial vasodilation associated with pregnancy and cirrhosis. Preliminary results from our laboratory and others suggest the possibility that nitric oxide may be a major mediator of the arterial vasodilation in pregnancy and cirrhosis. Different convergent methods will be used to evaluate this possibility and, if confirmed, to study the factors responsible for an activation or induction of nitric oxide synthase. Chronic oral blockage of nitric oxide production by a L-arginine competitive antagonist (nitro-L -arginine methylester) will be used in pregnant and cirrhotic rats to test the role of nitric oxide. Based on our body fluid volume regulatory hypothesis, the hemodynamic, renal and hormonal modifications observed in these states should be reversed, at least in part by nitric oxide blockade. In vitro vascular studies and molecular biology techniques will be used to confirm the activation or induction of the nitric oxide synthase. Other potential vasoactive substance sin cirrhosis will also be investigated using IL-1 receptor antagonists, endothelin antagonists and bradykinin antagonists.